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Toxic epidermal necrolysis

[version 1; referees: 3 approved]


Wolfram Hoetzenecker , Tarun Mehra , Ieva Saulite , Martin Glatz ,
Peter Schmid-Grendelmeier , Emmanuella Guenova , Antonio Cozzio ,
Lars E. French1

Dr. Arif Effendi Sp. KK

By : Dea Nabila Ratu Alicia


Abstrak

Toxic epidermal necrolysis (TEN) is a


rare, life-threatening drug-induced
skin disease with a mortality rate of
approximately 30%. The clinical
hallmark of TEN is a marked skin
detachment caused by extensive
keratinocyte cell death associated
with mucosal involvement.
Introduction

The exposure to drugs has increased with


demographic shifts associated with a higher
morbidity of the population. Along with this
phenomenon, a rise in the incidence of adverse
drug reactions (ADRs) has been observed. Toxic
epidermal necrolysis (TEN) is a rare, acute, and
life-threatening mucocutaneous disease that is
usually drug related. Recent evidence situates
TEN as the most severe form amongst a
spectrum of severe epidermolytic adverse
cutaneous drug reactions, which further include
Stevens-Johnson syndrome (SJS) and the SJS-
TEN overlap disease.
TEN is a consequence of extensive
keratinocyte cell death that results in the
separation of significant areas of skin at the
dermal-epidermal junction with the
production of bullae followed by skin
sloughing. This extensive cell death also
leads to mucous membrane detachment
and contributes to the characteristic
symptoms of TEN, which include high fever,
mucositis, and moderate to severe skin
pain, anxiety, and asthenia.
Clinical features
The main symptoms of TEN are usually preceded
by non-specific symptoms such as fever, stinging
eyes, and discomfort upon swallowing by several
hours up to several days.
Characteristically, cutaneous lesions first appear
in the presternal region as well as the face, palms,
and soles of the feet. Mucosal involvement occurs in
more than 90% of patients, predominantly affecting
the mouth, genitalia, and/or ocular region. In some
cases, the respiratory system and gastrointestinal
tract are also affected.
The morphology of lesions is characterized by
erythema and erosions. Ocular involvement is
frequent.
Figure 1. Toxic epidermal necrolysis (TEN) after carbamazepine
administration. (A) Skin detachment with facial erosions, including
involvement of the lips and conjunctiva. (B) TEN with an extensive cutaneous
involvement marked by detached and detachable apoptoticskin erosions on
the trunk
Pathogenesis
So far, the precise molecular and cellular
pathogenic mechanisms leading to the
development of SJS/TEN can be only
partially explained. It is thought to be
initiated by an immune response to an
antigenic drug-host tissue complex.
Figure 2. Conceptual models concerning T cell stimulation by drugs in Stevens-Johnson syndrome
(SJS)/toxic epidermal necrolysis (TEN). (A) Drugs inducing an adverse skin reaction are not antigenic
by themselves. Instead, their immunogenicity may result from binding to carrier proteins, which allows
the formation of neoantigens that are recognized by T cells upon presentation by antigen-presenting
cells (APCs). (B) The p-i concept is based on the pharmacological interactions of drugs with immune
receptors. Consistent with this concept, chemically inert drugs, which are unable to bind covalently to
proteins, may activate specific T cells by binding directly to T cell receptors and/or major
histocompatibility complex molecules. (C) The association of peptides with HLA molecules is highly
specific. According to the “altered peptide model”, specific HLA molecules form a complex with certain
drugs, thereby modifying the pool of self-peptides presented to T cells. This may result in increased
autoimmunity. Concepts for immunological responses of SJS/TEN modified from Abe et al.
Treatment
The suspect drug should be discontinued immediately
and supportive therapy should be ensured in the burn or
intensive care unit. However, valid data on effective
therapeutic options are poor, and prospective controlled
clinical trials, which can clearly show the benefit of certain
treatment options, are lacking. Some case reports and case
series report a benefit of cyclosporine, cyclophosphamide,
N-acetylcysteine, TNF-α antagonists (e.g. etanercept and
infliximab), systemic corticosteroids (favoring pulsed
corticosteroid treatment), thalidomide, plasmapheresis,
and intravenous immunoglobulin (IVIG).
Method
 performed skin patch testing to identify
the causative agent in 17 patients who
had suffered from SJS and/or TEN.
Positive patch test reactions were
observed in only 24% of those patients.
 The study was conducted at the
Dermatology department of the University
Hospital of Zürich, Zürich, Switzerland
Discussion
Conclusions.
 Since the time TEN was first described by Dr. Lyell, it
has remained a deadly disease with a mortality of
around 30%. There is an unmet need to study the
pathophysiology of TEN in more detail, which is
complicated by the rarity of this disease and the lack
of appropriate mouse models. Additionally, effective
therapeutic options validated by prospective,
randomized, controlled trials remain to be discovered.
The most important therapeutic measure so far
remains the rapid identification and withdrawal of the
causative drug in addition to supportive care.
However, this can be a complicated task inpatients
with polymedication. The allergologic work-up is
further.
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